Potentiation of tetracycline by phosphinic acid



United I States Patent.

n Edward Takesue, Pearl River, and Joseph John Hlavka,

L Ys -Xaeng lam silz cwai lBnethei-j Mqnty N .J., assignors to American Cyailamiii Company, New York, N .Y., a corporation "of Maine N0 Drawing. fiEiletl Dec-20, 1 960, Ser. No. 77,006

10 Claims; (Cl. 16755) ha areat qaiaeeae me w thiansa sqm q it a containing tetracycline antibiotics and" thei subs'tances which serve to promote absorption under physiological conditions thus resulting injhigher blood concentrations of antibiotic. w P H The use of the tetracycline antibiotics administered orally presents some prqb l ems where is desired 'to have the antibiotic penetrate theblood'streanifas in many cases there is considerable lossthrough poor absorption of antibiotic andithus-only-a portion appears in the blood,

In the past, various attenipts have been made to increase the blood levels obt ainedby oral fee ding ofrJetracycline antibiotics with various 'substances 'which have been generally referred to in the art as adjuvants. Typical of such substances, are .citric acid and its salts; various.

chelating agents, such as salts of'ethylenediamine tetraacetic acid; various inorganic,phosphates and tl e like. Recently, terephthalic acid 'be ii' iifopo sed *a's adjuvant, more particularly when tetracyclines are incorporat'ed in animal feied gand glucos amine has been proposed for human use;

According to the present" invention, we have found a group; ofucompoundsg whichl serve, tonpromote greater absorption of theantibiotic blood stream and exert a more powerful adjuvant ad a oipotentiating effect than twla qaili elasea a aqi eaetat r One of the best classes of (:0 "pounds useful in the 'present' invention are certain organg oxyphosphorous compounds which may be; represented: by the following general formula:

wherein R is a member of the group consisting of lower alkyl, hydroxylower alkyl, carboxylower' alkyl, carbalkoxylower alkyl, cyanolower alkyl, cyanohydroxylower alkyl, carboxyhydroxylowep'alliyl radicals, carbalkoxyhydroxylower alkyl and hydroxyphenyllower alkyl radicalsh One of the beStbCiIl IRRQUnd S of class is bis(l-icarboxy-.l-hydroxyethyl) phosphinic acid, monohydrate otherwise known as 2,,21-ph9spliinicgdilactic acid.

' Another class of highly; useful organo oxyphosphorous compounds are those organic jphosphonic acids orjesters which may be formula:

wherein R is a member of the'group consisting of phenyl,

henyl,Hihfiibxyisuenyruew I I alkylphenyl, carboxyphe'riyl,idicarboxylphenyl, ar'alkyl,

represented by the following general,

'(210) l-anilino-l-niethylethyDphosphinic acid ,,,,Patented Dec. 1, 1964 er. alkyl, allyl, and hydroxycarboxy lower aklyl radicals; and 1 is a member; 9251. 9 i rn psccgs sfin qi ihydt and lower alkyl ,radicals and salts thereof Other useful compounds according to the present invention v'v'ill be apfia'reiitir bni tlie detailed description hereinafter.

r y y m y pfcne yl, tu y yjd iqxymethy yd xy 10w-.

The ia e sfsrew ea atiheiadill a ts use u n. the present invention are shown below and ar numbered 1 to 40. For convenience these compounds will be referred to hereinafter with afiprgpriate numbers rather than the name or the formula,

STRUCTURAL OF USE 1 i i n (1) Bis (1 carboxy 1 hyd roxyetl 1yl)phosphinic acid monohydrate (2,2'-pli6spliiiiic6di1actic acid) 2 Bis(lehydrorgyel ineithylethylphosphinic.racid' T H (LE 2 p (4) Bis(2-carboxyethyl)phosphinic' acid [HO OG InC -hi -OH (5 Bis(2-cyanoethyl) phosphinic acid 5 1 O [No-on omqgi -on 6) Bis(a-hydroxyber iyl) phosphinicacid (7 Bis (hydroxyme thyl) acid 0 Y- -hydrpxypropyl)phosphinic acid (9) Dioctylphosphinic acid 3 (1 l) 1,2,3,4,5,6-hexahydroxyhexyl phosphinic acid 011 EOCH1(OHOH)4CH0H1L=O 1'; (2) Diethyl a-hydroxyfurfuryl phosphonate 13 Diethyl l-hydroxyheptyl phosphonate v cmc mcmomCmomi na-i b0 392 (14) Diethyl l-hydroxypropyl phosphonate on omt m-i (0 02m):

( 15 Diethyl allylphosphonate CHFCHCHFIIILI) (OCzHa): 16) Diethyl hydroxymethylphosphonate HO GH -i l (O CzHs): v

( 17 Diethyl Z-methylpropenyl phosphonat e CH CH=CHI l (O CrHz):

H3. 18) Diethyl benzylphosphonate (19) Diethyl 2,5-dihydroxyphenyl phosphonate (21) p-Aminophenylphosphonic' acid (22) p-chlorophenylphosphonic acid (23) Styrylph'osphonic acid (alkalion '4 (24) Diethyl p-methoxyphenylphosphonate Q z DI (25) Ethyl 4-ch1orophenyl Z-methylpropenyl-phospho- (26) l-carboxy-l-hydroxyethyl phosphonic acid 0 OH H E (I10),P I COOH (27) Phosphonophthalicacid, monopotassium salt (28) -Benzylphosphonic acid (29) Phenylphosphonic acid a fil) (30) 3,4-xylylphosphonic acid CH3 I EGG-1 (OH):

(31 Tris(Z-carhoxyethyDphosphine hydrochloride (HOOCCH CH P HCl 7 (32) Bis(2-carhoxyethyl) phenyl phosphine oxide o 7 Q-i omcmo 0 0H),

(33) Z-hydroxy-6-methy1-5-nitro cinchomeronic acid (IJOOH (34) S-bromoizihchomeronic acid COOH (35) Polyacrylic acid, molecular weight 250,000

Polyacrylic acid, molecular weight 50,000 Polyacrylic acid, molecular weight 10,000

I Hydrolyzed polyacrylonitrile g H (36 -a nof3-merca pto 3-methyI Y a I CH3 a 1 Him HCOOH i SH (37) Shikimic acid (boon 38-) carhoxymethylthiosuccinic; acid 99 HQQQCHNHQQOH 39 .Newss and:sa tnsntlna i .a v

rron,oN fl HO-fi -ooorr A-sulfophthalic acid 110 s COOH :QQOH

. .Certain of. the adjuvants listed. above are acidic coml pounds and are;shown in the form of their free acids. "They may saaesa'equau atwen'in the form of their simple saltssuchas the alkali metal 91.- emuloniumg-salts. 3Q.

In a particularly preferred-embodimentofthe-present invention it is contemplated thattetracycline-saltswith the above adjuvants and particularly with the organo ......oxyrp osphorous,,compounds of hesen ra nfiorrn l I .lab.ove,may be prepared and lused as such-afieca se m y or,theg abo eradjuvan s.are. a i i n na res y readily be combined in the form of a salt with artetracycline antibiotic .either astetracycline free base or as an acid addition salt, i.e., the hydrochloride. Thus,

for eXample,-.tetracycline.phosphinicodilactate has been The compositions of the present invention include any n 9f: he, tet acy ne an bio cs, n ud g te racy ne its f .(a br via Glpan ri ts tch as te acycline hydr :chlori e-(abb. ev at d1 TC-H .c-hl r y ine rey e TQ)... nd it sa s. s ch as es y rochlor i .h xytetra yc et bbre ia ed :Q ad methylc dr e racyc (abb eviat riDMCTQ-h deme hy a ycline "t r cycl e, ,7-bromo 6-d xy r y e tetra yc1ine,.. 9mitten-deoxyt cy -in -.:7.- irQ.- -d Y' ,1 tetracycline, -amino 6-dernethyL6 -deoxytetracycline, 9-

breviated DMTC) and various derivatives, such as the ,--.f 1 owingt tracy linec mnqunds; deem/tetracyc n ,.d n yl; 63.dew/te ra yc lrbrom rd me hyl-6- deoxytetracycline, 7;-.-,. hloro 6V,,- demethyl=6rdeo etraamino-G-demethyl-6rdeoxytetracycline, 9-aminow6-deoxytet'racycline, 9 1 amino 7-bromofi deoxytetracycliue, 9-

1 deem/ tracy l n 7: -..-bromoi,- 5- y r yrnadeoxy etra ydemethyl 6 deoxytetracycline, 7.: bromo-Q-nitrg-ddeniethyl-6-deoxytetracycline, 9 -arnino-7-chloro-6-demethyl- 6-deoxytetracycline, 7-chloro-9-nitro-6-demethyl-6-deoxytetracycline.

.The eXPression ftetracycline antibiotic? as usedthroughout the specification and claims is intended toembrace ny o he. orego n te racy e 0 nn9n .It is to ekunderst qd. at:th ne-l e r y i es w ch enommer al rrpnt nt y ommer dr g h as. chlort etr cyo e, et acycl ne;qxy racyc e, dem t y tetracycline and demethyltetracycline are lespeeially preferred because of their readyavailability and demonstrated wclinical usefuln ,The method of administering the compositions of the present inyention to mammals isquitevaried. Aqueous solutions may be employed and this modification includes the addition of the compositions of the present invention .prepared byreacting equal.mol ..quantities ot-tetracyol-iue and 2,2-phosphinicodilactic acid. This.comp, ound aswell compounds and tetracycline antibiotic. V i If desired, these'novelcompositions mayhavensefully added thereto a di fliere nt adjuvant either alone or as a salt such as the sodium onammonium salt thereof or With an added tetracycline antibiotic either as the free base orin the formofgaidifier h rsalt such as he .e y chloride. ,AlSQ, -..desired,.;;difierent combinations of vbeprep ared. It is not known how the novel adjuyants operate to enhance the-blood concentration ofitetracycline anti.- .biotics. Ihey.. arechemicalh' soQMdely-d fierent.. tha it may .well hetha'lt different mechanisms operate with difhfe rent; adju'vants. Their. chemicaldifierences are. so marked that they are not in any sense chemically equivalent, {their 'only.equivalenoefbeing in" the. fact that they are all adjuvants andthey all;rai;sefthe blood concentra- L tion of tetracycline. antibiotics: theory as tq why..'these 'idiverseUco'mpounds ope'arte' inthis'pnannef'is advanced r '3 and it is not intended that thepresent inanimate limited to, any particular theoryof action;

to water infthe case of animals wvhich.obtain. their .water' from a central ,sour'ce. The .inixture of the..two ,sub-

stances as a suspension or dispersion in highly flavored extracts orinsolid form is also useful; Solutions for itintr'ave'n'ous or solutions orhsuspensions for intramuscular -i. ;administrations are possible., For feXample,-. the adjuvant 45...

and, thertetracycline, antibiotic with an inert excipient may be enclosed in hardor soft-shell gelatin capsules or they may be compressed intq tablets or incorporated with animalfeeds. 'In general, the method of administering I ecn npQsit Qn o the P e ent; i vention; d es: ot p fr m the c nv tio al-mea Qtadminist ins t racy ra o sq hi is a v n ed t rr se tinvent and the improvedres ul re,obtained Without requiring a. special technique of administration.

The preparation of 'tetracysline antibiotic to adjuvant may vary over fairly Wide limits; Preferably the adjuvant is present in amounts ranging from 0.1 to 10 parts by Weight, with optimum results being obtainedin amounts of from 0,1 to 3parts by weight. 7

A dosage unit i'orm fororal .administrationto humans .isflmost conveniently apowdered. mixture of..the. anti- H biot n-and. hea inv nte c s asclat n n A tetracycline antibioticsvwithlone ormore adjuvants may' do e n t. f rmu as cqn ain ro abq t 5 t 00 so of ned s ed. etracycl ens h r ,1 3

parts by weight or more gf adjuyant An inert diluent such as starch, sucrose, or magnesium stearatemay be added if desired. A preferred composition consists of 150-250 mg. of a tetracycline antibiotic, together with 500 mg. of an adjuvant in a soft gelatin capsule.- Similarly, dosage unit forms o-f-the novel tetracycline, organo oXy-phos-phorous salts may be prepared in any convenient manner and containing the requisite therapeutic l; Idoseof antibiOtic. 'Ifdesired, thec'ompositions maybe Qgranullated and administered 'as such,,or may be com-- i i pressed into tablets suitable for oraladministration. Also,

if desiredtacomposition can be formulated into numerous and various other conventional pharmaceutical forms of medication. These will be administered by the attending physician or veterinarian in accordance with the age and condition of the patient, nature of the disease and in view of the other considerations peculiar to the individual patient.

In the following examples, dilferent controls are used in each case because comparison techniques for tetracycline antibiotics are considered most accurate when given in the same period. This standard procedure is followed in the examples and explain why there will be a variation in blood levels of animals used in control experiments. In each example, the important thing is not the absolute numerical value of the blood level, but the value of the blood level relative to the control in the particular example. In the examples, the abbreviations for the various tetracycline antibiotics set out above will be used to facilitate ease of understanding and the adjuvants will be abbreviated Adj followed by the number of the adjuvant substance.

EXAMPLE 1 Groups of the same number of albino rats, ranging in weight from 175 to 300 grams, were dosed orally with a solution or suspension of 50 mg./kg. of tetracycline hydrochloride via a feeding needle. Similar groups received a mixture of 50 mg./kg. of TC-HCl. plus 140 mg./ kg. of known adjuvants. The serum levels obtained four hours following administration are shown in the following table:

It will be noted that citric acid and terephthalic acid result in substantial increase in serum level but glucosamine, which has been used extensively, does not result in any significant difference.

EXAMPLE 2 The experimental conditions of Example 1 were repeated using fresh groups of rats and including a fresh control group. The results appear in the following table:

TABLE 2 Dose, Blood 7 Substance mg./kg. levels,

meg/ml.

TO-HCI 4. 70 TOHCl plus terephthalic acid 50+140 7. 29 'IO-HCl plus Adj 1 50+140 13. 73

It will be noted that Adjuvant 1 gives a much greater blood level increase than does terephthalic acid and about three times the blood level of the control dosed with tetracycline hydrochloride alone.

8 EXAMPLE 3 The procedure of Example 1 was repeated with new groups of rats. The results appear in the following table:

TABLE 3 Substance It will be noted that very substantial increases in blood level resulted from Adjuvant 1.

EXAMPLE 4 It will be noted that both Adjuvants 27 and 11 result in a substantial doubling of blood levels, even though here also the controls showed unusually high concentrations.

EXAMPLE 5 The procedure of Example 1 was repeated with a smaller amount of adjuvant. The results appear in the following table:

TABLE 5 Dose, Blood Substance mgJkg. levels,

meg/ml TC-H 60 4.87 TC-HCI plus Adj l1 60+50 8. 20 TO-HOl plus Ad] 1 50+50 13. 94 TO-HOI plus Adj 27 50+50 9. 93

It will be apparent that there is a substantial increase with all of the adjuvants but Adjuvant 1 shows greater enhancement that any of the others.

EXAMPLE 6 The experimental conditions of Example 5 were repeated with larger groups of rats and included a large number of adjuvants together with the known citric acid, terephthalic acid and glucosamine.v The results appear in the following table:

TABLE 6 Blood Compara- Substance Dose level, tivc ratio,

. meg/ml. TC =1 TC-HCl 50 mgJkg 1. 38 1 TC-HCl plus citric acid 50 mg./kg. of each"..- 1.35 0. 9 TO-NOl plus terephthalic acid 50 mgJkg. oi cach. l. 66 1. 20 TC-HC1 plus glucosaminc HOl. 50 mg./kg. of each 1.87 1.35 'lC-HCl plus Adj. 29,; 50 mgJkg. of each" 2. 06 1.49 TO-HOl plus Adi 27 50 rug/kg. of eac 2. 50 1.81 TO-HOI plus Adj 1.-. 50 mg./kg. of each-.- 3. 88 2. 81

It will be noted thatdthe blood level increases follow It will be noted that in this example, blood levels at 1 the same pattern but her e-citrie acid';is-distinctly poorer Va i s hours after admin strat on j e en a e dif- -i--thanterephthalic acid-=and-aetually no betterthan the m r nt. s asyc mq qsh r ,qmtqs a er patt r of --c0ntrol,-whereas-glucosamine shows some increase. i fid bl 2 lWlSWih-A j V 5 ,EXAMBLE 11 "Y-EXAIVIPLE 7 i Adjuvant l iwas te d inn ogsr group o ,;-Ih ee;d v. being L a nt and a -..vnum er of itetraey li s- .employ Here n, as nl' he presed nglexamp ehlzl o lleyel at different hours appear. It will be noticed that the dose 0 Thattheinorganiosalts oflAdjuvant- '1 elicitfarresponse as great as the free acid is illustrated by the result-sgiven below,the-experimentalprocedure-followed-being -sirnilar 10 in the dogs is only half-the relative dose in rats. The

to Example 5. 7 results are shown in the following table:

. TABLE 11 v Myer-I Substance 3 Dose 7 N V7 p ,1 hrs- ,,5 hrs. hrs

H 1 2.17 1.62 r 1.32 TQ'HOLplusAdj 1 8.12v 6.12 1 4.35 s TO 0.74 1.00 1, 0.84 DMCTC plus Adj 1- 8.4 4. 84 s 3. 52 DMTC 1146 0.53 0.40 I DMIC plusAdjl 11.32 7.22 f 4.5

TABLE 7 I EXAMPLE- 12 V I 4H0 The procedure of Epga r ples l and 2 Was repeated exsppstance Dose I fieru n geptthat tetracycline sulfate was employed instead of a fgf gi 'tet'racyoline hydrochlorider The rs ults 'are' as fo llowsz TABLE 12 I ,3.64 i Dose, eBlood Siubstance v mg./kg. levels,

n peg /ml.

Tornso 50 2.9 As asnappareut h0th Ad3uYant and. 1 ts. s0o1um salt T032803 plus aim 50+140 ..l--were.ver y-eflect1ve inamncreasmgtthe absorption ofetetraomsm plus Adj 1- 50+140 11.3

cychne- "EXAMPLE 8 a. 1 e ult ppearing in e allo i g table:

Itwill be seen that the tetracycline sulfate when'used j, The procedure of Xalnple 5 was repeated with the withAdjuyant l gives substantlally hetter results when V onipared with citric acid. The anion of tetracycline TABLE 8 .saltsisinotlthereforesparticularly. significant.

' WNEXAMPLE l3 s The procedure .of Example. 1 .wasrepeated with a num- Dose, Substance rpg/kg.

v 50 28 used in each control test. The results appear in the folmo-lror i s d aqn V +140 lowing table:

'TABLE 13 EXAMPLE 9 H d The procedure of, Example 5 was again followed with 4, Substance i ,Dose, W Adjuvant 1 and citric"acid and two additional tetra- 50 s/ g- .gAdjuvant 1 and several othervtetracyclines. The results cyclines. The results appear in thefollowing table:

I i TABLE!) r Blood level,

i Substance Dose '1 v meg/r111. $04101 plus Adj 13 TG-HC1 plus Adj 5. 'IC-HClplus Adj 17 IQQ'IC-HCLplus Adj l9 TO-HCl plus Adj 18 c. TC-HOI plus Adj 25 TO-HCl plus Adj 4 "EXAMPLE '10 Q; The procedure ofv Example 5 was -followed with ber of; additionahadjuvantsand 50ml grams'offte'traappear in the following table: i

' TABL 10 a :S i'uhstance- Dose ,7

, propanol.

11 EXAMPLE 14 The procedure of Example was repeated using 50 milligrams of tetracycline per kilogram of body weight as the control and using 50 milligrams of tetracyline per kilogram of body Weight and 50 milligrams of adjuvant per kilogram of body weight in the test compounds. The results obtained are shown in the table below:

TABLE 14 Serum Meg/ml. Substance levels, of TC-HCl meg/ml. on same test TO-HCl plus polyacrylic acid M.W. 10,000.-.. 6. 32 3. 56 TC-HCI plus polyacrylic acid M.W. 50,000 5. 75 3. 56 TC-HO1 plus polyacrylic acid M.W. 100,000-.. 5.85 3. 56 TO-HG1 plus polyacryllc acid M.W. 250,000... 6. 89 3. 56 TC-HC1 plus hydrolyzed polyacrylonitrile 4. 26 3. 52 4. 65 2. 02 6. 34 2.01 5. 76 3.85 6. 21 4. 62

EXAMPLE 15 The procedure of Example 1 was repeated using different adjuvants. In the control tests tetracycline hydrochloride was used at the level of 50 milligrams per kilogram of body weight and in the tests with the adjuvants '50 milligrams of tetracycline per kilogram of body weight and 140 milligrams of adjuvant per kilogram of body weight were used. The results are shown in the table below:

TABLE 15 Serum Meg/ml.

Substance levels, of TC-HCl mcgJml. on same test TC-HOl plus Adj 36 8.11 4. TC-HCI plus Adj 26 9.22 2.90 TC-HCl plus Adj 33- 7. 15 1. 17 TC-HCl plus Adj 38 5.60 2.49 'IC-HOI plus Adj 37 4. 12 1.17

EXAMPLE 16 Demethyltetracycline Phosphinicodilactate A mixture of 8.6 g. of G-demethyltetracycline in 350.

milliliters of isopropanol was heated to boiling and filtered through a heated filter.. To the clear filtrate was added a solution of 10.4 g. of 2,2'-phosphinicodilactic acid in 50 milliters of hot isopropanol. The resulting mixture was cooled in an ice bath and a solid separated. This was filtered and Washed first with 50 milliliters of cold isopropanol followed by 3 x 100 milliliters of ether;

yield 8.5 grams.

Analysis.Calculated for C H N O P: C, 48.2; H, 4.9; N, 4.2; P, 4.6. Found: C, 47.5; H, 5.6; N, 4.2; P, 4.6.

EXAMPLE l7 Tetracycline Phosphinicodilaclate To a warm solution of 22.2 g. of tetracycline free base in 500 milliliters of isopropanol was added 26 g. of 2,2- phosphinicodilatic acid in 100 milliliters of warm iso- On cooling a solid separated; yield, 25.3

grams.

Analysis.-'-Calculated for C H N O P: C, 49.0; H, 5.1; N, 4.1; P, 4.5. Found: C, 48.4; H, 5.8;-N, 3.3; P, 4.8.

EXAMPLE 18 Demethylchlortetracycline Phosphinicodilactat e Five hundred milligrams of demethylchlortetracycline was dissolved in S milliliters of isopropanol-and 500mil- 12 I ligrarns of 2,2-phosphinicodilactic acid was dissolved in 4 milliliters fo isopropanol, each by heating as necessary. The solutions were mixed and filtered hot and after cooling in ice the product was filtered oil? and washed with cold isopropanol and ether. Weight 350 milligrams.

Analysis.-Calculated for C H N ClO P: C, 45.9; H, 4.6; CI, 5.0; P, 4.4. Found: C, 45.96, 45.74; H, 5.40, 5.56; CI, 4.73; P, 4.26.

In a similar manner by reacting substantially equivalent quantities of oxytetracycline or chlortetracycline with 2,2-phosphinicodilactic acid, there may be obtained oxytetracycline phosphinicodilactate and chlortetracycline phosphinicodilactate, respectively.

EXAMPLE 19 The procedure of Example 1 was repeated under the same conditions but using the new tetracycline salts of Examples 16, 17 and 18, respectively. The results obtained are shown in the table below:

TABLE 19 Blood level cone. in rats, 'y/ml.

I. Demethylchlortetracycline phosphinicodilactate 5.8 Demethylchlortetracycline (alone) 3.0 Demethylchlortetracycline plus 2,2'-phosphinicodilactic acid (mixture) 4.7

II. Demethyltetracycline phosphinicodilactate 11.6 Demethyltetracycline (alone) 6.6 Demethyltetracycline plus 2,2'-phosphinicodilactic acid (mixture) 8.2

III. Tetracycline phosphinicodilactate 4.7 Tetracycline (alone) 3.3

It will be observed that the new tetracycline salts gave superior blood levels as compared to the antibiotics alone or in admixture with 2,2'-phosphinicodilactic acid.

This application is, in part, a continuation of our copending application, Serial No. 826,110, filed JulylO, 1959, now abandoned.

We claim:

1. A composition of matter comprising a tetracycline antibiotic and as a potentiating agent therefor from 0.1 to 10 parts by weight of a phosphinic acid of the formula:

(mai -OH wherein R is a member of the group consisting of lower alkyl, hydroxylower alkyl, carboxylower alkyl, carboalkoxylower alkyl, cyanolower alkyl, cyanohydroxylower alkyl, carboxyhydroxylower alkyl, carbalkoxyhydroxylower alkyl and hydroxyphenyllower alkyl.

2. A composition according to claim 1 in which the compound is 2,2'-phosphinicodilactic acid.

3. A composition of matter comprising a tetracycline antiobiotic and as a potentiating agent therefor from 0.1 to 10 parts by weight of a phosphonic compound of the formula:

5. A composition of matter comprising a tetracycline antiobiotic and from 0.1 to 10 parts by weight of bis(2- carboxyethyl) phenyl phosphine oxide.

6. A composition of matter for the potentiation of an orally administered tetracycline antiobiotic demethyltetracycline phosphinicodilactate.

7. A composition of matter for the potentiation of an orally administered tetracycline antibiotic, tetracycline phosph nicodilactate.

8. A composition of matter for the potentiation'of an orally administered tetracycline antibiotic, demethylchlortetracycline phosphinicodilactate.

9. A composition of matter for the potentiation of an orally administered tetracycline antibiotic, oxytetracycline phosphinicodilactate.

14 10. A composition of matter for the potentiation of an orally administered tetracycline antibiotic, chlortetracycline phosphinicodilactate.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Editorial, N. Eng. J. 'Med., vol. 258, No. 2, page 97, January 9, 1958. 

1. A COMPOSITION OF MATTER COMPRISING A TETRACYCLINE ANTIBIOTIC AND AS A POTENTIATING AGENT THEREFOR FROM 0.1 TO 10 PARTS BY WEIGHT OF A PHOSPHINIC ACID OF THE FORMULA: 